Glaucoma is one of the leading causes of preventable blindness, and currently available treatments are not sufficient to halt progression in many patients. While much has been learned about the biology of glaucoma, development of new forms of treatment has been stymied by three barriers: high between-subject variability in ganglion cell number in normal eyes, high within-subject variability in patients with glaucoma, and the slow rate of progression of the disease. The proposed research integrates neural modeling and clinical research to develop improved methods for diagnosing glaucoma and for assessing progression towards blindness. The results are intended to improve measures for both clinical trials and ongoing patient care, while at the same time improving basic science understanding of the pathophysiology of glaucoma and providing guidance for biological studies of the disease process. Innovative uses of clinical devices will guide testing with custom systems, and statistical analyses will utilize the synergy between structural and functional measures of glaucomatous damage. High-resolution retinal imaging of retinal nerve fiber layer (RNFL) will be performed on patients with glaucoma using a custom advanced adaptive optics scanning laser ophthalmosope (AOSLO) as well as custom use of spectral domain ocular coherence tomography (SD-OCT). High-resolution perimetry will be performed in corresponding regions of the visual field, using custom stimuli that are resistant to optical artifacts that affet conventional perimetry. The results will be assessed with innovative statistical methods that utilize the synergy between perimetry and imaging measures. Specific Aim 1 will apply these methods to people free of eye disease, building three-dimensional models of RNFL that capture both structure and thickness, with the goal of using structure to overcome the barrier of high between-subject variability in ganglion cell number in normal eyes. Specific Aim 2 will focus on temporal retina, which has unique characteristics that make it possible to locate where retinal nerve fibers begin, starting with just a few axons. Temporal retina corresponds to nasal visual field, where visual field loss is common in early glaucoma, and the emphasis will be on detecting some of the earliest changes in a longitudinal study. Specific Aim 3 will focus on the macula, which is of great importance because it provides high-resolution vision used for many activities of daily living. The macula also has unique characteristics that make it possible to image the starting locations of retinal nerve fibers, and is well-suited for high-resolution perimetry. Specific Aim 4 will extend this approach to nasal retina, by examining patients with wedge RNFL defects that are narrow at the optic disc and then widen in a wedge of damaged RNFL. Whereas Specific Aims 2 & 3 address unique locations where RNFL fibers begin, Specific Aim 4 will address how to interpret RNFL defects across the rest of the retina.